tbuckley/cabot-search huggingface dataset:
PB1995: SAFETY OF SUBCUTANEOUS DARATUMUMAB IN MULTIPLE MYELOMA: A RETROSPECTIVE MULTI-CENTER REAL LIFE EXPERIENCE
Authors: D. De Novellis, A. Carobene, R. Fontana, L. Mettivier, F. Trastulli, S. Rocco, S. Palmieri, M. Di Perna, A. Pagano, V. Giudice, C. Califano, F. Ferrara, C. Selleri
Journal: HemaSphere (2022)

Background: Daratumumab, an anti-CD38 monoclonal antibody, is approved for Multiple Myeloma (MM) treatment at an intravenous (IV) dosage of 16 mg/kg with high rates of infusion-related reactions (IRR; 45-56%), especially at the first infusion. However, the subcutaneous (SC) formulation has shown comparable efficacy with lower IRR risk and with shorter administration time (3-5 minutes) compared to IV daratumumab as reported in PAVO (NCT02519452), COLUMBA (NCT03277105) and PLEIADES (NCT03412565) clinical trials. Approved SC daratumumab dosage is 1800 mg, independently from patient variables including renal failure or body weight. Aims: Here, we investigate safety of SC daratumumab in different MM regimens in a multi-center real-life experience Methods: A total of 29 MM patients (Table 1) who received at least one dose of SC daratumumab at 1800 mg in any association regimen since December 2021 was included in this retrospective study. Enrolled patients were daratumumab-naïve starting directly with SC formulation combined with any association regimen displayed in Table 1. Primary end point was SC daratumumab safety, especially for IRR incidence and severity. Results: All patients received premedication with dexamethasone, paracetamol and antihistamine according to current guidelines and montelukast was used in 23 out of 29 (79%) cases. Median number of SC administrations for single patient was 3 (range 1-10), and administration time ranged from 3 to 5 minutes. One patient (3%) experienced grade III IRR in two consecutive administrations, and grade I hematological and grade I gastroenteric toxicities (diarrhea) were observed in 3 (10%; 2 thrombocytopenia and 1 neutropenia) and 1 (3%) cases Image:Summary/Conclusion: In our multicenter retrospective experience, SC daratumumab showed high safety with a very low (3%) IRR rate, even inferior to that reported in PAVO and PLEIADES trials, despite we included in our study patients with renal failure, different body weights or without montelukast premedication. Of note, IV daratumumab induced IRR especially during the first exposition, while we reported a very low IRR rate with SC daratumumab also during first administrations (median number of cycles, 3). The only patient with grade III IRRs weighted 65 kg, did not have renal failure and did not receive montelukast premedication. The patient was switched to IV daratumumab without further IRR suggesting an SC formulation excipient-related intolerance rather than daratumumab-induced reaction. However, IRR incidence was low to analyze hypothetical associations between predisposing factors and IRR insurgence. In conclusions, our real-life findings showed that SC daratumumab is very manageable with an excellent safety profile and very short administration time. Further validation on larger and prospective clinical studies are needed
P1662: OPTIMIZED PROPHYLAXIS BASED ON INDIVIDUALIZED TARGET TROUGH FVIII LEVEL IN PEDIATRIC PATIENTS WITH SEVERE HEMOPHILIA A
Authors: K. Huang, Z. Chen, R. Wu, Y. Zhen, G. Li
Journal: HemaSphere (2022)

Background: Due to the great inter-individual variability of pharmacokinetics and bleeding phenotype among children with severe hemophilia A(SHA), individualized prophylaxis is urgent and vital. Aims: To investigate the effectiveness of our new-proposed PK-guided, trough level escalating dosing regimen. Methods: Pediatric patients with SHA were enrolled. They followed a PK-guided, trough level escalating protocol. PK tests were conducted with a five-point assay to calculate individualized PK profiles. During the two-year period, clinical assessments were conducted every six months, including joint bleeds, ultrasound(US) scores and Hemophilia Joint Health Score(HJHS) of ankles, knees and elbows. A quantitative scoring system based on the above-mentioned clinical assessments was used to determine the necessity of trough level’s escalation. Results: Fifty-eight SHA boys were finally analyzed. Their age and body weight were 5.3(2.8,6.9)years and 21.5(16,25)kg respectively. At baseline, 34 of them had a trough level of <1IU/dL and the number remained 10 at study exit. During the study period, 47 escalations were observed. The most frequent reason was joint bleeds(59.6%, N=28). Significantly reduced annualized bleeding rate[0(0,6) vs. 4(0,8),P<0.0001] and annualized joint bleeding rate[0(0,0.25) vs. 0(0,2),P<0.0001] was observed at study exit as well as the continuous trend of decreased bleeding rates. Zero bleeding rate and zero joint bleeding rate raised from 27.6% to 69% and 46.5% to 81.3% respectively. In addition, 85%(6/7) of the target joints vanished at study exit. Statistical improvements of US scores(P=0.04) and HJHS scores(P=0.02) were also reported at end of study. Image:Summary/Conclusion: This protocol individualized target trough level and optimized clinical outcomes in pediatric patients with severe hemophilia A.
P1716: REGULAR HOSPITAL VISITS IMPROVE THE PROGNOSIS OF MULTIPLE MYELOMA PATIENTS
Authors: X. Li, J. Liu, B. Huang, J. Gu, J. Li
Journal: HemaSphere (2022)

Background: Multiple myeloma（MM）is a common hematological cancer. The overall survival rate of individuals with MM has risen significantly in the previous decade, primarily as a result of the advent and advancements of innovative treatments. As a consequence, given the possibility that cancer will progress to the stage of chronic illness, the post management and regular hospital visit of MM patients are particularly important. Although it seems that long term chronic disease management by regular hospital visit has increased medical expenditure, from the perspective of whole process treatment, it is the best way to achieve standardized treatment and monitoring and may improve the prognosis of MM patients The regular hospital visits means regular hematologist visits with regular treatment and monitor. Irregular hospital visits means visits to other hospital divisions or with no hospital visits. Aims: The aims of this study were to investigate the relationship between regular hospital visits and prognosis of MM and to suggest methods to avoid poor prognoses in MM. Methods: We performed a multicenter retrospective analysis of data from 832 MM patients across 9 centers in China from 2006 to 2020. Sociodemographic (including whether regular hospital visits) and clinical factors at diagnosis and treatment regimens were recorded, and univariate and multivariate analyses were performed. Results: Overall, 30.3% of patients had irregular hospital visits. Patients with irregular hospital visits levels differed from those with regular hospital visits in that they were more likely to be older, and a higher proportion lived in rural areas, were unemployed, and with lower education levels, had lower annual incomes and lacked insurance. Additionally, compared to patients with regular hospital visits, patients with irregular hospital visits had a higher proportion of international staging system (ISS) stage III classification, time to diagnosis is longer and underwent transplantation less often. Patients with regular hospital visits had a median progression-free survival (PFS) of 52.04months, which was better than that of patients with irregular hospital visits (20.3 months, p < 0.001). Similarly, patients with egular hospital visits had a median overall survival (OS) of 107.4months, which was also better than that of patients with irregular hospital visits (37.1 months, p < 0.001). In the multivariable analysis, patients with regular hospital visits had lower relapse rates and higher survival rates than did those with irregular hospital visits in terms of PFS and OS (hazard ratio (HR) = 1.95, p < 0.001; HR =2.80, p < 0.001, respectively). Summary/Conclusion: Irregular hospital visits may independently predict poor survival in MM patients in China.
PB2098: ‘REAL-WORLD’ TREATMENT PATTERNS AND PATHWAYS OF SECOND LINE DIFFUSE LARGE B-CELL LYMPHOMA PATIENTS IN UK, CANADA, FRANCE, GERMANY, ITALY AND SPAIN USING A PROSPECTIVE SURVEY OF PHYSICIANS
Authors: A. Bailey, N. Milloy, I. Sanderson, J. Butcher, C. Spooner, D. Kilic, S. Vadgama
Journal: HemaSphere (2022)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent form of Non-Hodgkin Lymphoma, representing 25% to 35% of cases annually1. Despite this, there is a lack of research into treatment patterns of real-world patients, especially in the 2nd line (2L) setting. Aims: To determine the ‘real-world’ treatment patterns and treatment pathway of DLBCL patients treated at the second line, with a focus on patients who are ‘fast progressors’ as defined below. Methods: In this study ‘real-world’ data were drawn from the Adelphi DLBCL Disease Specific Programme™ (DSP), a point-in-time survey of clinicians and their next 6 presenting patients with DLBCL. The survey was conducted in France, Germany, Italy, Spain, the United Kingdom (UK) and Canada between Jan-May 2021. Patients who were refractory/relapsed <12 months from 1st line (1L) therapy, eligible for a stem cell transplant (SCT) at initial relapse/refractory, had an ECOG performance score of 0-1 and had no history of hepatitis B or C or CNS events were studied. Results: 47 patients met the criteria. Mean age of the patients was 58.0 (SD: 11.7) years, 68% were male and 26% were retired. At 1L, 94% of patients received R-CHOP with a median of 171.2 days (IQR: 61.0-247.5) between the end of their 1L and the start of their 2L treatments. All patients received salvage chemotherapy (SC) in the form of R-ESHAP, R-DHAP or R-GDP in most cases (Figure 1). 49% of the patients had a complete response (CR) to SC, 21% had partial response (PR), 30% stable/no response. In total 26 (55%) patients received high-dose therapy-SCT (HDT-SCT). Figure 1 shows the response to 2L treatments across patients and indicates why some patients did not progress to SCT despite being previously eligible. Patients receiving SCT had a median time from 2nd line SCT to relapse/refractory of 189.0 (IQR: 94.0-333.0) days. 54% of patients received chimeric receptor antigen T-cell (CAR-T) therapies at 3L (Figure 1), with the majority having previously received SCT. CAR-T use was higher in UK (67%), Canada (63%) and Germany (60%) than in other regions. Image:Summary/Conclusion: Despite all patients with DLBCL observed being SCT eligible at their first relapse, only half of these patients went on to receive an SCT. Unacceptable response to SC, progressive disease and patient choice were common reasons for not going on to receive SCT. Despite seemingly favourable responses to SCT, these patients progressed quickly and were likely to receive a CAR-T treatment in 3L, indicating an unmet need and highlighting potentially high resource use and substantial impacts to quality of life.
Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study
Authors: Kristina E N Clark, Eszter Csomor, Corrado Campochiaro, Nicholas Galwey, Katherine Nevin, Mary A Morse, Yee Voan Teo, Johannes Freudenberg, Voon H Ong, Emma Derrett-Smith, Nicolas Wisniacki, Shaun M Flint, Christopher P Denton
Journal: The Lancet Rheumatology (2022)
P1305: HSA_CIRC_0001599 REGULATES IL18 LEVELS IN AGVHD VIA CERNA MECHANISM
Authors: M. Xia, J. Zhang, Y. Dong, X. Lv, X. Cui
Journal: HemaSphere (2022)

Background: AGVHD (acute graft-versus-host disease) is one of the major complications after hematopoietic stem cell transplantation, and severe aGVHD not only seriously affects the outcome of transplantation but also may pose a threat to the patient’s life.The gastrointestinal system is one of the areas most strongly affected by aGVHD. Aims: This study was dedicated to investigating the pathogenic mechanism of hsa_circ_0001599 in intestinal acute graft-versus-host disease (aGVHD). Methods: Four patients with intestinal aGVHD and four healthy volunteers were invited to have peripheral blood drawn early in the morning on an empty stomach. After treatment, peripheral blood mononuclear cells (PBMCs) were obtained, and after further testing and purification, RNAs that met the experimental requirements were obtained from them. After screening circRNAs with abnormal expression levels by high-throughput sequencing as well as data processing, the levels of specific circRNAs in 20 patients were verified by qRT-PCR. Then, the ceRNA interaction network was constructed by bioinformatics analysis using GO, KEGG and miRanda. Finally, clinical patients’ correlations were analyzed to determine the sensitivity and specificity of disease-related indicators for disease diagnosis. Results: 1. High-throughput sequencing results showed that a total of 330 circRNAs showed bidirectional expression in the aGVHD group relative to the HC group, of which 8 were up-regulated and 322 were down-regulated (FC≥2.0, P≤0.05) (Figure 1 A). 2. PCR validation of high level expression of hsa_circ_0001599 The PCR results showed that the mean expression level of hsa_circ_0001599 in the aGVHD group was more than twice that of the control group. (Figure 1 B) 3. Analysis of differentially expressed genes involved in intestinal aGVHD and pathway prediction Analysis by GO and KEGG enrichment indicated that the upregulation of circRNA expression may have an impact on the pathogenesis of intestinal aGVHD (Figure 1 C). 4. Construction of circRNA-miRNA-mRNA interaction network The hsa_circ_0001599-targeted mRNA: IL18 was predicted using miRanda, TargetScan and other databases, and the ceRNA interaction network was constructed (Figure 1 D). 5. We analyzed the relationship between clinical characteristics, hsa_circ_0001599 and IL18 in 15 patients with intestinal aGVHD. The results showed that the level of hsa_circ_0001599 was positively correlated with IL18 level in intestinal aGVHD patients.(R2=0.832, P<0.05). (Figure 1 E) Image:Summary/Conclusion: The aberrant expression of hsa_circ_0001599 in PBMCs may be a new diagnostic marker and therapeutic target for intestinal aGVHD.
P1655: PERSONALIZED MACHINE-LEARNING-BASED PREDICTION FOR CRITICAL IMMUNE THROMBOCYTOPENIA BLEEDS: A NATIONWIDE DATA STUDY
Authors: Z.-Y. An, Y.-J. Wu, R.-B. Huang, H. Zhou, Q.-S. Huang, H.-X. Fu, Q. Jiang, H. Jiang, J. Lu, X.-J. Huang, X.-H. Zhang
Journal: HemaSphere (2022)

Background: The rare but important critical bleeding events in primary immune thrombocytopenia (ITP) are life-threatening complications in ITP patients, severely affecting their prognosis, quality of life, and treatment decisions. However, critical ITP bleeds, including intracranial haemorrhage and some gastrointestinal bleeding and respiratory bleeding, have not been adequately studied. This suggests an unmet need for personalized patient management strategies and an urgent need for effective tools to predict the risk of critical ITP bleeds in hospitalized patients in medical practice. Aims: The aim of this study was to develop a clinical prediction model based on a nationwide multicentre study in China on behalf of the National Cooperative ITP Working Group, integrating clinical and laboratory data. Methods: We first conducted a multicentre, retrospective cohort study with consecutive unselected inclusion of ITP inpatients from 8 medical centres in China from December 2002 to September 2019. After the development and external validation of the model using machine learning algorithms, we established a prospective observational cohort of 37 medical centres across China from November 2021 to January 2022 to further assess model efficacy. The study was registered at ClinicalTrials.gov (NCT05116423). Results: We built a model including 9 simple predictors, including the initial PLT count, age, age at onset, infection, ITP type, skin and mucosa bleeding, low PLT count (below 20*109), uncontrolled diabetes, and cardiovascular disease. Through the development and validation of nine different machine learning algorithms, the random forest algorithm outperformed the others. The random forest algorithm reached an area under the receiver operating characteristic (ROC) curve (AUC) of 0.901 in independent external validation. The model showed good calibration capabilities, and the decision curve analysis showed a high average of predicted net benefit in the risk threshold range of 0-95%. The model is presented in the form of a web application (http://47.94.162.105:8080/mavenitp/). The model in further prospective validation at 37 medical centres nationwide showed an AUC of 0.776, demonstrating good predictive efficacy. Image:Summary/Conclusion: Our findings suggest that this machine-learning-based model based on 9 simple and easily available predictors provides good performance in predicting the occurrence of critical bleeds in ITP patients and has demonstrated good efficacy in a national multicentre prospective validation. A web-based online tool based on this algorithm rapidly identifies the bleeding risk profile of ITP patients to support clinical decision-making and reduce the occurrence of adverse outcomes.
P1416: DNA DAMAGE TRIGGERS A P53 INDUCED AGEING RESPONSE IN HAEMATOPOIETIC STEM CELLS
Authors: M. Wang, L. Brandt, X. Wang, J. Garaycoechea, N. Wilson, B. Göttgens, K. J. Patel
Journal: HemaSphere (2022)

Background: Ageing of haematopoietic stem cells (HSC) has been frequently observed as reduced self-renewal capacity and differentiation bias towards the myeloid and away from lymphoid lineages. However the physiological drivers, and the molecular mechanism of HSC ageing is poorly understood. We have previously discovered that mammalian cells produce toxic levels of aldehydes that are a physiological source of DNA damage to HSCs. Protection from genotoxic aldehydes critically rely on detoxifying enzymes (ALDH2 and ADH5) and the Fanconi anaemia (FA) DNA repair pathway. Children born with genetic deficiencies in ALDH2 and ADH5, or the FA pathway develops bone marrow failure and leukaemia due to attrition of HSCs. Given the ubiquitous nature of aldehydes in our own body, can aldehydes contribute to the ageing of HSCs in haematopoiesis? Aims: 1. Assess whether genotoxic aldehydes accelerate and recapitulate features of ageing in haematopoiesis. 2. Dissect the molecular mechanism of how aldehyde-DNA damage triggers ageing in haematopoiesis. Methods: We utilised the Aldh2-/- Fancd2-/- mouse model, where combined deficiency in the aldehyde detoxification enzyme Aldh2, and the FA DNA repair pathway (Fancd2) causes accumulation of aldehyde-induced DNA damage in HSCs. To assess for evidence of aged HSCs, we subjected Aldh2-/- Fancd2-/- mice to: 1. Single cell RNA sequencing (scRNAseq) of haematopoietic stem and progenitor cells to characterise for transcriptome features of ageing and to identify differentially regulated pathways that may underpin such changes. 2. Direct quantification of aged HSCs through immunophenotyping and use of genetic reporters in Aldh2-/-Fancd2-/- mice. 3. Functional interrogation of the renewal and differentiation capacity of Aldh2-/- Fancd2-/- HSCs using single HSC transplantation analysis. Results: Analysis of 8 weeks old Aldh2-/- Fancd2-/- HSCs revealed features of accelerated ageing, harbouring an aged transcriptome signature similar to 24 months old wild-type HSCs, and myeloid biased haematopoiesis. To investigate the origins of the myeloid biased stem and progenitor cells, we introduced the Vwf-GFP genetic reporter into Aldh2-/- Fancd2-/- mice to find enrichment for Vwf+ longterm HSCs previously shown to be biased towards megakaryocytic and myeloid differentiation. We found strong activation the p53 pathway in Aldh2-/- Fancd2-/- HSCs, which enabled the definition of an single cell transcriptome atlas of the p53 network in haematopoiesis. Strikingly, genetic deletion of p53 in Aldh2-/- Fancd2-/- mice rescued the accelerated ageing and myeloid bias shown by both scRNAseq and transplantation of single HSCs. Image:Summary/Conclusion: DNA damage from endogenous aldehydes in HSCs activates p53 to trigger accelerated ageing and drives differentiation towards myeloid lineage. This pathway may have evolved to cleanse DNA damaged stem cells and maintain the HSC pool.
Abstract LB116: CXCL8/Interleukin-8 orchestrates radiation-induced immune responses in pancreatic adenocarcinoma
Authors: Thomas Walle, Joscha A. Kraske, Boyu Liao, Carmen Timke, Benedicte Lenoir, Niels Halama, Peter E. Huber
Journal: Cancer Research (2022)

Abstract The role of radiotherapy in the treatment of pancreatic adenocarcinoma (PDAC) is controversial. In many other tumor types, radiotherapy is a mainstay therapy whose anti-tumor effects have partially been ascribed to T cell responses. The role of Natural Killer (NK) cells in radiotherapy tumor responses remains unclear. Here, we focused on the role of NK cells in radiotherapy of pancreatic cancer. In a randomized controlled pancreatic cancer trial, we found that CXCL8 serum levels increased under radiotherapy and NK cells positively correlated with prolonged overall patient survival. Accordingly, NK cells preferentially infiltrated irradiated tumors and exhibited CD56dim like cytotoxic transcriptomic states. In preclinical experimental systems in mice and tumor cells, NF-κB and mTOR signaling prompted radiation-induced CXCL8 secretion from senescent tumor cells causing directional migration of CD56dim NK cells into tumors. Thus, we link senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy which may be integrated into PDAC treatment algorithms. Citation Format: Thomas Walle, Joscha A. Kraske, Boyu Liao, Carmen Timke, Benedicte Lenoir, Niels Halama, Peter E. Huber. CXCL8/Interleukin-8 orchestrates radiation-induced immune responses in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB116.
Reply to W. Attaallah, A. Jain et al, and P. Mroczkowski et al
Authors: Eva Versteijne, Jacob L. van Dam, Marc G. Besselink, Bas Groot Koerkamp, Marjolein Y.V. Homs, Johanna W. Wilmink, Casper H. van Eijck, Geertjan van Tienhoven
Journal: Journal of Clinical Oncology (2022)